Busulfan/cyclophosphamide in volunteer unrelated donor (VUD) BMT: excellent feasibility and low incidence of treatment-related toxicity

An increasing number of volunteer unrelated donor bone marrow transplantations (VUD-BMT) are performed every year for hematological malignancies due to the availability of a large donor pool. Here we show the results of 36 VUD transplants from our institution using a chemotherapy-only conditioning regimen comprising busulfan 4 x 4 mg/kg and cyclophosphamide 2 x 60 mg/kg. All patients received heparin 200 IU/kg bw continuous i.v. infusion starting the day before conditioning until day +30. Thirty-four of 36 patients (94%) engrafted and no secondary graft failure was observed. The two non-engraftments occurred in patients with CML in blast crisis with extensive myelofibrosis. All 34 engrafted patients (100%) were in complete remission on day +30 as shown by bone marrow biopsy and cytogenetic examinations. No life-threatening treatment-related morbidity or mortality (TRM) were observed, in particular, no severe veno-occlusive disease (VOD) of the liver and no fatal pulmonary complication. Use of G-CSF significantly shortened the time of neutropenia by 5 days. GVHD prophylaxis consisted of CsA/methylprednisolone with or without MTX. Acute GVHD grade II-IV was observed in 18/34 patients (53%) and cGVHD in 12/27 patients (45%), who survived to day +100. In seven patients (four with HLA class I or II mismatch) anti-T-lymphocyte globulin (ATG) was added for acute GVHD prophylaxis. One of seven had aGVHD grade II and none developed grade III to IV GVHD or graft failure. We conclude that Bu/CY is a feasible, save and sufficiently immunosuppressive regimen for VUD transplantation. Severe acute GVHD might be avoided by additional use of ATG in GVHD prophylaxis.     

Allogeneic marrow transplantation for myelodysplastic syndrome with advanced disease morphology: a phase II study of busulfan, cyclophosphamide, and total-body irradiation and analysis of prognostic factors

PURPOSE: To determine if an intensive preparative regimen of busulfan (BU), cyclophosphamide (CY), and total-body irradiation (TBI) could improve outcome after marrow transplantation for advanced morphology myelodysplasia (refractory anemia with excess blasts [RAEB], RAEB in transformation [RAEB-T], and chronic myelomonocytic leukemia [CMML]) compared with that obtained with conventional CY/TBI and to analyze prognostic factors for transplantation for myelodysplasia. PATIENTS AND METHODS: A phase II study was conducted of 31 patients (median age, 41 years) treated with BU (7 mg/kg), CY (50 mg/kg), TBI (12 Gy), and human leukocyte antigen (HLA)-matched (n = 23) or -mismatched (n = 2) related or unrelated donor (n = 6) marrow transplantation. Results were compared with 44 historical control patients treated with CY (120 mg/kg) and TBI. RESULTS: The 3-year actuarial disease-free survival (DFS) rate was similar for the BU/CY/TBI group and the CY/TBI group (23% v 30%, P = .6), but there were trends toward lower relapse rates (28% v 54%, P = .27) and higher nonrelapse mortality rates (68% v 36%, P = .12) among the current patients compared with historical controls. Multivariate analysis showed that a normal karyotype pretransplant and the use of methotrexate as part of posttransplant immunosuppression were associated with improved survival and reduced nonrelapse mortality. Univariate analysis showed significant differences in relapse rates based on marrow source (57% for HLA genotypically matched marrow v 18% for all others, P = .04) and on disease morphology (66% for RAEB-T v 38% for RAEB and CMML, P = .05). CONCLUSION: Patients with advanced morphology myelodysplasia tolerated the intensified BU/CY/TBI preparative regimen and reduced posttransplant immunosuppression poorly. Novel transplant procedures are needed to reduce relapse rates without increasing nonrelapse mortality rates. In addition, transplantation before progression to RAEB-T, if possible, may reduce the risk of relapse.     

Autologous bone marrow transplantation in acute myeloid leukemia: the University of Minnesota experience

PURPOSE: To report the outcome of autologous bone marrow transplantation for patients with acute myeloid leukemia (AML) in first or greater complete remission (CR) treated by autologous bone marrow transplantation using two different preparatory regimens. METHODS AND MATERIALS: Between September 1986 and August 1993, 75 patients with AML ranging in age from 6 months to 58 years underwent autologous bone marrow transplantation using previously harvested and frozen unpurged (n = 6) or 4-hydroperoxycyclophosphamide purged marrows (n = 69). Patients were in first CR (n = 44) or beyond first CR (n = 31). The preparative regimen consisted of 120 mg/kg of cyclophosphamide (CY) and 1320 cGy total body irradiation (TBI) in eight fractions over 4 days (CY/TBI) in 29 patients; and 16 mg/kg of Busulfan (BU) and 200 mg/kg of CY (BU/CY) in 46 patients. Thirty-five of these 75 patients (18 CY/TBI and 17 BU/CY) were part of a randomized trial comparing the two preparative regimens. RESULTS: At 2 years, overall survival and disease-free survival (DFS) were 49% [95% confidence interval (C.I.) 37-61%] and 43% (95% C.I. 32-55%), respectively. Patients in first CR had a significantly better outcome than patients beyond first CR with an estimated 2-year DFS of 59% (95% C.I. 44-74%) vs. 21% (95% C.I. 5-36%, log-rank p = 0.0001), respectively. For patients conditioned with CY/TBI, the estimated 2-year DFS was 52% compared to 39% for BU/CY (log-rank p = 0.35). Estimated 2-year relapse rates were 44% vs. 56% (log-rank p = 0.40), respectively. For patients in first CR, no differences in DFS were observed between the two regimens (2-year estimates 69% vs. 55% log-rank p = 0.52). Patients beyond first CR had a significantly improved DFS with the CY/TBI regimen (2-year estimates of 38% vs. 7%, log-rank p = 0.04). No differences were found between the two regimens in terms of time to WBC engraftment, absolute neutrophil count of > 500, incidence of bacteremias, or median time to hospital discharge. Interstitial pneumonitis developed in two patients (one BU/CY, one CY/TBI) and venoocclusive disease developed in seven BU/CY patients (Fishers exact test p = 0.04). CONCLUSIONS: For patients beyond first CR, the CY/TBI regiment provided a better outcome, with a significantly better disease-free survival and less venoocclusive disease. For patients in first CR, no significant difference between the two regimens was found. The high relapse rate, especially for patients with advanced disease, emphasizes the need for early transplantation and for new strategies to improve outcome.     

Oral combination antiemetics in patients with small cell lung cancer receiving cisplatin or cyclophosphamide plus doxorubicin

BACKGROUND: Intravenous antiemetic combinations containing a 5-HT3 receptor antagonist (like metoclopramide, ondansetron, or granisetron) with dexamethasone have become the standard therapy for the treatment of acute chemotherapy-induced vomiting. Intravenous antiemetics, however, can be more costly and take more time to prepare and deliver, and therefore are not preferred for home, outpatient, or office use. The objective of this study was to determine the antiemetic activity and safety of the oral combination antiemetic regimen of metoclopramide, dexamethasone, and diphenhydramine in patients with small cell lung cancer receiving standard outpatient chemotherapy programs. METHODS: Fifty-two patients receiving initial cisplatin (60 mg/m2) or cyclophosphamide (600-1500 mg/m2) plus doxorubicin (30-45 mg/m2) received an oral regimen of metoclopramide (3 mg/kg x 2 then 2 mg/kg x 2 or 4 doses), dexamethasone (20 mg) and diphenhydramine (50 mg x 2 or 3 doses) (oral MDD), beginning 30 minutes before chemotherapy. RESULTS: Vomiting was prevented in 15 of 21 (76%) patients (95% confidence interval [CI], 53%-92%) receiving cisplatin and 21 of 31 (71%) individuals (95% CI, 52%-86%) given cyclophosphamide plus doxorubicin. Adverse effects were mild and transient and included sedation, loose stools, akathisia, and hiccoughs. CONCLUSIONS: The oral MDD antiemetic regimen prevented acute emesis in 73% of the patients entered and was well tolerated in this population of patients with small cell lung cancer.     

Busulfan-based regimens and allogeneic bone marrow transplantation in patients with myelodysplastic syndromes

Preparative regimens containing busulfan (BU) followed by allogeneic bone marrow transplantation (BMT) were used in 27 consecutive patients with myelodysplastic syndromes (MDS). The median age was 33 years (range, 4 to 54). Ten were female and 17 male. Sixteen patients had primary MDS, 11 other patients had antecedent hematologic diseases or developed MDS after cytotoxic and/or radiation therapy. Six patients had leukemic transformation and received antileukemic therapy before BMT. Pre-BMT cytogenetic studies showed complex chromosomal abnormalities in 13 patients, a simple abnormality in 5 patients, and normal chromosome in 8 patients. Three BU-based preparative regimens were used: 1 patient received BU 4 mg/kg orally (PO) daily for 4 days and cyclophosphamide (CY) 50 mg/kg intravenously (IV) daily for 4 days (BUCY-4); 24 patients received BU 4 mg/kg PO daily for 4 days, cytosine arabinoside (ara-C) 2 g/m2 IV every 12 hours for 4 doses, and CY 60 mg/kg IV daily for 2 days (BAC); and 2 patients with preceding Fanconi anemia received BU 2 mg/kg PO daily for 4 days followed by total lymphoid irradiation of 5 Gy. Seventeen of 27 patients are alive with no evidence of disease. Ten patients have died: 2 from hepatic veno-occlusive disease, 3 from sepsis, 1 from a cerebral bleed, 1 from a massive gastrointestinal (GI) bleed associated with acute graft-versus-host disease, 1 from hemolytic uremic syndrome with adult respiratory distress syndrome, 1 from bronchiolitis obliterans, and the only patient who did not engraft died from acute myeloid leukemia. Regimen-related toxicities (RRT) include GI tract (diarrhea, 14; stomatitis, 11), liver (9), cardiac (1), and skin (5). Patients who received a genotypically matched marrow graft had a significantly better disease-free survival (DFS) than patients who received a nongenotypic marrow graft (P = .02). The Kaplan-Meier analysis projects an overall DFS of 56% +/- 13% and 78% +/- 10% for patients who received a genotypically matched marrow graft. With the exception of a child who did not engraft, there was no relapse of MDS or leukemia. Excellent DFS, acceptable RRT, and the ease of administration are advantages of this regimen.     

A lymphoma cell line resistant to 4-piperidinopiperidine was less sensitive to CPT-11

The purpose of the study was to assess the toxicity and efficacy of an oral, combination antiemetic regimen including granisetron (Kytril; SmithKline Beecham Pharmaceuticals, Philadelphia, PA, USA) in the setting of highly emetogenic conditioning chemotherapy for stem cell transplantation. Antiemetic prophylaxis consisted of oral granisetron 2 mg once daily, oral prochlorperazine 10 mg q 6 h and oral dexamethasone 4 mg q 6 h, beginning 1 h prior to chemotherapy on each of the 4 days of chemotherapy and continuing until 24 h after the completion of high-dose chemotherapy (HDC). Patients received either CVP (cyclophosphamide 6 g/m2, VP-16 1800 mg/m2 and carboplatin 1200 mg/m2) or CTP (thiotepa 500 mg/m2 in place of VP-16) in four daily doses given over 4 h from days -4 to -1. Previously mobilized and cryopreserved peripheral blood stem cells (PBSC) were reinfused on day +1. Evaluation of nausea, emetic episodes (EE), adverse events, and rescue medications were recorded on a daily patient diary. Thirty-six patients were entered. Fifty-three percent (95% CI = 37-75%) of patients achieved complete response for emesis (CR = 0 EE/24 h) and 75% (95% CI = 58-90%) had combined complete and major response (CR+MR = 0-3 EE/24 h) during all 5 of the treatment days. During the 5 study days, the average number of patient-days with no emesis was 3.7 (74%) and with 1-3 EE was 4.3 (86%). On days -4, -3, -2, -1 and 0, the combined CR+MR rate for emesis was 97, 92, 86, 78 and 75%, respectively. Nausea was absent or mild on all 5 study days in 57% (95% CI = 37-75%). Eight patients had severe late-onset emesis occurring on days +1 to +3 after reinfusion of stem cells. No clinically significant toxicities attributable to the antiemetic regimen were observed. An all oral antiemetic regimen of granisetron, prochlorperazine and dexamethasone appears to be safe and highly effective in patients receiving multiple, daily, high-dose chemotherapy regimens. This regimen offers the advantage of cost-savings, a low side-effect profile and ease of administration in the predominately outpatient setting of HDC with peripheral blood stem cell transplant (PBSCT).     

The role of thiotepa in autologous bone marrow transplantation for acute leukemia

Post-transplant leukemic relapse remains the major problem following autologous bone marrow transplantation (ABMT). One possible approach to reducing the relapse rate is to intensify pre-transplant conditioning. Thiotepa (TTP) is an alkylating agent that has been used mainly in breast and ovarian cancer with 20-50% response rates. This report presents our results on 33 patients with acute leukemia (acute myeloblastic leukemia (AML) 27 patients, acute lymphoblastic leukemia (ALL) six patients) who underwent ABMT following conditioning with busulfan (BU), 4 mg/kg x 4 days (days -8 to -5), TTP 5 mg/kg x 2 days (days -4, -3) and cyclophosphamide (CY) 60 mg/kg x 2 days (days -2, -1). Of the 33 patients, 22 were males and 11 females, of median age 24 (1-55) years. Twenty-eight patients were transplanted in complete remission (AML 26; ALL 2) while 5 (AML 1; ALL 4) were in early relapse. Twenty-nine additional AML patients (15 females, 14 males) of median age 22 (2-48) years, who underwent ABMT following a standard BU-CY conditioning regimen (25 in complete remission and four in relapse) served as historical controls. There were no significant differences between the study and control groups with respect to patient age, sex, diagnosis, stage of disease, FAB classification, and prior chemotherapy, at ABMT. Overall survival, disease free survival (DFS), and relapse rate at 72 months were 33, 33 and 61%, respectively, for the study group, and 38, 34.5 and 52%, respectively, for the historical controls. Engraftment and transplant related toxicity also did not differ significantly in the two groups. In conclusion, TTP appears to have made no substantial improvement to the outcome of ABMT for acute leukemia.     

Massive pleural effusion attributed to high-dose cyclophosphamide during conditioning for BMT

A 37-year-old male developed massive pleural effusion leading to respiratory failure and electromechanical dissociation within 24 h after the second dose of 4200 mg cyclophosphamide (CY) during conditioning for allogeneic bone marrow transplantation for chronic myelogenous leukemia. After resuscitation and bilateral pleural drainage he recovered within 1 day. Subsequently, total body irradiation was given and with a delay of 1 day the transplantation procedure was continued without major complications. No explanation for this idiosyncratic reaction other than the administration of high dose CY in combination with mesna rescue was found. This reaction has not been reported before in the literature.     

The balance hypothesis of renin release

Successful allogeneic hematopoietic transplants require conditioning regimens with sufficient immunosuppression to allow acceptance of the allograft. Cyclophosphamide, in combination either with TBI or with chemotherapeutic drugs, is the keystone of commonly used regimens. The toxicities of TBI and tumor resistance to cyclophosphamide create a niche for alternative, chemotherapy-based conditioning regimens. We report successful allogeneic stem cell transplantation after an ifosfamide-based regimen with ifosfamide 20 g/m2, carboplatin 1.8 g/m2 and etoposide 3 g/m2 (ICE) in divided doses over 6 days. Engraftment was prompt with neutrophils > or = 20 x 10(9)/l on day +10 and platelets > 20 x 10(9)/l on day +18. Engraftment of donor cells was documented by chromosome analysis and by VNTR analysis. An ifosfamide-based regimen provides sufficient immunosuppression for hematopoietic allograft acceptance in the absence of cyclophosphamide or of TBI.     

Successful pregnancy after conditioning with cyclophosphamide and fractionated total body irradiation

We report the case of a 24-year-old man who received high-dose cyclophosphamide (CY) 120 mg/kg over 2 days and twice daily fractionated total body irradiation (TBI) over 3 days(1,320 cGy) prior to allogeneic bone marrow transplantation. Seven and one-half years later he fathered a normal child who has developed normally so far.     

Women''s anger: relationship of suppression to blood pressure

Myeloablative therapy followed by allogeneic bone marrow transplantation (BMT) has proven to be curative therapy in patients with hematologic malignancies. Relapse, however, remains a major cause of treatment failure for patients with advanced disease. During the past 15 years, we have gained considerable experience with the combination of fractionated total-body irradiation (FTBI) and etoposide followed by allogeneic BMT for hematologic malignancies. In an attempt to decrease post-transplant relapse rates, 67 patients under the age of 50 years with high-risk or advanced-stage hematological malignancies received an intensified regimen of FTBI and etoposide plus cyclophosphamide followed by BMT from a genotypically-matched related donor. The regimen consisted of 1320 cGy of FTBI in 11 fractions, 60 mg/kg of etoposide (VP-16), and 60 mg/kg of cyclophosphamide (CY). Fifty-three patients received cyclosporine and prednisone for graft-vs.-host disease (GVHD) prophylaxis and 14 patients received cyclosporine, methotrexate, and prednisone. Diagnosis at BMT included 45 patients with acute leukemia, 7 patients with chronic leukemia, and 15 patients with high-grade non-Hodgkin's lymphoma (NHL). Actuarial disease-free survival (DFS) at 3 years was 42% +/- 12% for the entire group with a median follow-up of 50 months (range 20-74) for 28 patients who remain alive in continued complete remission (CR). Actuarial 3-year-DFS was 38% +/- 14% in 52 patients with acute or chronic leukemia and 60% +/- 25% in 15 patients with NHL with relapse rates of 45% +/- 16% and 21% +/- 11%, respectively. DFS at 3 years was 40% +/- 18% in 32 patients with acute leukemia in 1st relapse or 2nd CR or chronic myelogenous leukemia in accelerated phase, and was 32% +/- 22% in 20 patients with more advanced disease. Regimen related mortality occurred in 9 patients (4, veno-occlusive disease of the liver; 2, multi-organ failure; 1, diffuse alveolar hemorrhage; 1, central nervous system (CNS) hemorrhage; 1, adult respiratory distress syndrome (ARDS). The combination of FTBI, etoposide, and cyclophosphamide followed by allogeneic BMT is an effective and relatively well-tolerated regimen for patients with advanced hematologic malignancies. The role for this regimen should be further defined by prospective clinical trials.     

Big BU/CY is associated with a favorable long-term outcome in patients allotransplanted for chronic myelogenous leukemia in chronic phase

Twenty-six adult patients, median age 36 years (range 21-53) with chronic myeloid leukemia in first chronic phase were allotransplanted between October 1989 and May 1995. The preparative regimen consisted of busulphan 16 mg/kg and cyclophosphamide 200 mg/kg (big BU/CY). Cyclosporin A and methotrexate were used for GVHD prophylaxis. Twenty-two donors were HLA-identical siblings and four donors were mismatched for one antigen of class I. The global incidence of acute GVHD was 50%, that of severe aGVHD (grades 3-4) was 11%; the global incidence of chronic GVHD was 30%. No patients developed veno-occlusive disease of the liver or interstitial pneumonia. Five patients died, one of relapse, four of transplant-related causes, mostly related to aGVHD; thus, the transplant-related mortality was 16%. Twenty-one patients are alive, in remission, with a median follow-up of 55 months (range 24-90); actuarial probability of survival is 78% (CI 64-96). Our study shows that this conditioning regimen is relatively easy to administer and seems to be as effective as, if not superior to, regimens containing TBI, in patients with chronic myeloid leukemia in chronic phase and the transplant-related mortality is not excessive even in older patients.     

Thought control strategies in acute stress disorder

Relapse after transplant for malignant lymphomas remains the main cause of treatment failure. Most conditioning regimens contain total body irradiation (TBI). We investigated the toxicity and efficacy of an intensified chemotherapy conditioning regimen without TBI in patients with relapsed or high-risk malignant lymphoma who had received prior radiation therapy and were therefore not eligible for TBI. Twenty patients with a median age of 38 (18-56) and relapsed or high-risk malignant non-Hodgkin's lymphoma (NHL, n = 16) or Hodgkin's disease (HD, n = 4) underwent high-dose chemotherapy consisting of busulfan (16 mg/kg), cyclophosphamide (120 mg/kg) and etoposide 30 mg/kg (n = 8) or 45 mg/kg (n = 12) followed by peripheral stem cell support (n = 14), autologous bone marrow (n = 3), allogeneic (n = 2) or syngeneic (n = 1) transplantation. All but two had chemosensitive disease before high-dose chemotherapy. The main toxicity -- according to the Bearman score -- was mucositis II in 18 (90%) patients; five patients (25%) suffered a grade I hepatic toxicity. GI toxicity I occurred in three (15%) and renal toxicity I in two patients (10%). Sixty percent of the patients developed transient dermatitis with erythema and three of them (15%) had skin desquamation; one patient experienced asymptomatic pancreatitis. Toxicity was slightly higher in patients treated with 45 mg/kg etoposide. One patient (5%) died of treatment-related venoocclusive disease. After a median follow-up of 50 months (24-84) the disease-free and overall survival were 50% and 55%. One of the nine relapsing patients developed secondary AML 18 months after transplant. High-dose busulfan, cyclophosphamide and etoposide is an effective regimen resulting in long-term disease-free survival in 50% of patients with relapsed malignant lymphoma and prior radiation therapy. The toxicity is moderate with a low treatment-related mortality (5%).     

Review of the preclinical pharmacology and comparative efficacy of 5-hydroxytryptamine-3 receptor antagonists for chemotherapy-induced emesis

PURPOSE: This analysis was undertaken to review published reports of the comparative efficacy and safety of 5-hydroxytryptamine-3 (5-HT3) receptor antagonists in the prophylaxis of acute chemotherapy-induced emesis. METHODS: Comparison data used are the preclinical pharmacology as well as the design and results of clinical trials. Seven comparative studies that used granisetron, ondansetron, or tropisetron in patients who received either moderately or highly emetogenic chemotherapy are reviewed. As the study designs, patient population, chemotherapy, antiemetic doses and schedule, and methods of assessment were slightly different, the results of each study are analyzed independently. Effectiveness is assessed by emetic episodes, nausea, and patient preference. RESULTS: The preclinical pharmacologic profile is different among the 5-HT3 antagonists in terms of potency, selectivity, dose response, and duration of action. The comparative clinical trials show that a single intravenous (i.v.) dose of granisetron 3 mg is as effective as multiple (8 mg x 3) or single (32 mg) i.v. doses of ondansetron for the prevention of acute nausea and emesis due to cisplatin. In the two moderately emetogenic clinical trials, granisetron 3 mg i.v. was at least as effective as ondansetron 8 mg i.v. +/- 24 mg orally and tropisetron 5 mg i.v. Patient preference was evaluated in three of the four crossover trials: granisetron was preferred in three of four, and no preference was reported in the fourth. The one trial to compare ondansetron 0.15 mg/kg x 3 versus granisetron 10 micrograms/kg x 1 or granisetron 40 micrograms/kg i.v. demonstrated equivalent control of nausea and vomiting in patients who received cisplatin-based chemotherapy. CONCLUSION: The 5-HT3 receptor antagonists compared are highly effective antiemetic agents that have now become the standard of care for preventing chemotherapy-induced emesis. Whether the described preclinical differences among these agents are also clinically significant remains to be seen. In the comparative trials analyzed, the 5-HT3 receptor antagonists demonstrated relatively equivalent clinical efficacy. Cost analysis may favor the use of one agent over another depending on the emetogenic challenge, dose of the 5-HT3 antagonists, and number of doses recommended. Patient preference may be an important factor to be considered in future antiemetic trials.     

Low transplant mortality in allogeneic bone marrow transplantation for acute myeloid leukemia: a randomized study of low-dose cyclosporin versus low-dose cyclosporin and low-dose methotrexate

Sixty patients undergoing allogeneic bone marrow transplant for acute myeloid leukemia (AML) in first remission (CR1; n = 49) or more advanced phase (n = 11) were entered in a prospective trial of graft-versus-host disease (GvHD) prophylaxis: low-dose cyclosporin A (IdCSA; 1 mg/kg/d from day -1 to +20 day; n = 28) or IdCSA plus low-dose methotrexate (IdMTX; 10 mg/m2 for day +1, 8 mg/m2 for days +3, +6, and +11; n = 32). Primary end points were acute GvHD (aGvHD) and transplant-related mortality (TRM); secondary end points were relapse and survival. The conditioning regimen consisted of cyclophosphamide (120 mg/kg) and fractionated total body irradiation (3.3 Gy/d for 3 consecutive days). The actuarial risk of developing aGvHD grade II-III was 61% for IdCSA alone and 34% for IdCSA + IdMTX (P = .02). The actuarial risk of TRM at 1 year was 11% versus 13%, respectively, and older patients (>/= 29 years) had higher TRM than younger patients (22% v 5%, P = .01). The age effect was significant in the IdCSA group (P = .04) but not in the IdCSA + IdMTX group (P = .1). The median follow-up is 4.4 years, with an overall actuarial survival of 78% for CR1 patients and 36% for patients with advanced disease. For patients in CR1 the outcome of the two regimens was as follows: survival 77% versus 80% (P = .6), relapse 20% versus 9% (P = .1), and TRM 13% versus 17% (P = .6). This study suggests that TRM can be reduced in AML patients undergoing allogeneic marrow transplants with a mild conditioning regimen and low-dose immunosuppression, and this translates in a 78% 5-year survival for CR1 patients. Beyond CR1 the major obstacle remains leukemia relapse, which is not prevented by low-dose in vivo immunosuppression.     

Transplantation of allogeneic peripheral hematopoietic progenitor cells instead of bone marrow

In a pilot study we tested the feasibility and safety of peripheral blood precursor cells instead of bone marrow cells for allogeneic transplantation. 13 patients, 7 male and 6 female between 24 and 52 years of age with hematological malignancies (10 with acute leukemias, 3 with myeloproliferative syndromes-were conditioned for bone marrow transplantation with VP-16, cyclophosphamide and total body irradiation followed by graft-versus-host disease prophylaxis with cyclosporin and methotrexate. Precursor cells were mobilized in the donors by granulocyte colony stimulating factor (G-CSF, Neupogen) 10 micrograms/kg s.c. from day-5 on. A total of 14.05 x 10(8) nucleated cells/kg recipient body weight (range 9.52-20.23 x 10(8)/kg), corresponding 6.82 x 10(6)/kg CD 34+ cells (range 1.43-15.84 x 10(8)/kg) or 113.9 x 10(4) CFU/kg (range 45.15-431.64 x 10(4)/kg) were collected by 3 phereses (1 patient 5 phereses) of 27-45 liters and infused without further manipulation. All patients engrafted with a recovery of total white blood cell count > 1 x 10(9)/l on day 15 (day 10-26) and of platelets > 20 x 10(9)/l on day +18 (day 12-39). 11 of the 12 patients developed aGvHD, 8 with grade II, 3 with grade > or = II. 9 of 13 patients are alive and well +4 to +16 months posttransplant, 3 patients died of aGvHD, one of veno-occlusive disease. These preliminary results confirm the capacity of peripheral blood precursor cells for rapid and complete engraftment in the allogeneic setting. Whether they induce more or equal aGvHD is an open question. Their value in allogeneic transplantation is currently under investigation in prospective randomized trials.     

Hematopoietic cell transplantation in the twitcher mouse. The effects of pretransplant conditioning with graded doses of busulfan

The effects of congenic hematopoietic cell transplantation (HCT; transplantation of bone marrow and spleen cells) after graded doses of busulfan (BU), a myeloablative but nonimmunosuppressive alkylating agent, were evaluated in the twitcher mouse model of human galactosylceramidase deficiency, a demyelinating sphingolipid storage disease. C57BL/6 twitcher mice (immunophenotype Ly-5.1) were given 10 to 50 mg/kg of BU or total-body irradiation (9.0 Gy) at age nine days and HCT from congenic Ly-5.2 donors 24 hr later. The 30-day post-HCT survival, an indicator of tolerance of the preparative regimen, was at least 83% in twitcher mice given 45 mg/kg or less of BU, was 50% in recipients of 50 mg/kg BU and 75% in TBI-conditioned twitchers. The lifespan of twitcher mice given HCT after 10 or 20 mg/kg of BU was similar to that of untreated twitchers (median survival, 42 days; range, 30-47). In contrast, mice transplanted after 35 to 50 mg/kg of BU had significantly prolonged survival (median, 82 days; range, 56-208) and stabilization of hindlimb paralysis, similar to TBI-conditioned recipients. Post-HCT repopulation by donor Ly-5.2 cells was determined by flow cytometry. Thirty days after HCT, only 11-15% of lymphohematopoietic cells in blood, bone marrow, and spleens were of Ly-5.2 donor origin in twitcher mice transplanted after 10 mg/kg of BU but 60-80% were of Ly-5.2 donor origin in mice transplanted after higher doses of BU. These levels further increased to 70-90% by 90 days after HCT, comparable to that seen after TBI. Levels of galactosylceramidase in livers, spleens, and brains of twitchers transplanted after 35-50 mg/kg of BU or after TBI increased to 30-116% of normal control values by 90 days after HCT. Conditioning for HCT with as little as 35 mg/kg of BU provides minimal peritransplant mortality, rapid and sustained establishment of donor lymphohematopoiesis, replacement of lysosomal hydrolase, and prolonged survival in this murine model of human sphingolipidosis.     

Antiemetic efficacy of granisetron in pediatric cancer treatment--(2). Comparison of granisetron and granisetron plus methylprednisolone as antiemetic prophylaxis

A crossover clinical trial was carried out to compare the effectiveness and safety of granisetron alone (40 micrograms/kg) with that from a combination of granisetron plus methylprednisolone (MPL, 10 mg/kg) for control of emesis and vomiting induced by anticancer drugs in children with cancer. Complete control of emesis and vomiting were achieved in 95% (19/20 cases) of patients receiving the combination compared to 85% (17/20 cases) of patients receiving granisetron alone. There were no clinical toxicities or side effects in either treatment group. These data indicated that the combination of granisetron plus MPL was superior for control of emesis and vomiting in children receiving cytostatic anticancer drugs.     

Control of emesis by intravenous granisetron in breast cancer patients treated with 5-FU, epirubicin and cyclophosphamide

Granisetron, a potent and selective 5-hydroxytryptamine receptor (5-HT3) antagonist was reported to be an effective antiemetic agent both in animal studies and in patients given highly emetogenic chemotherapy. A sample of 43 patients with breast cancer was accrued from September to November 1992 in a phase II study to assess the efficacy of granisetron in patients receiving FEC (5-FU, epirubicin, cyclophosphamide). Each patient received 3 mg intravenous granisetron as a single dose just prior to chemotherapy. Oral metoclopromide was prescribed to each patient as a rescue anti-emetic. The emetic episodes and degree of nausea were evaluated on a daily basis. Good control of emesis (0-2 episodes of vomiting) and nausea (mild or no nausea) was in the range 77%-98% and 77%-93% respectively. There was a complete response (no emetic episodes throughout the 6-day period) in 16 patients (37.2%). Onset of emesis tends to occur on day 1 and tend to subside after day 3; 85% of patients had onset of emesis in the first 2 days after chemotherapy. Control of emesis and nausea tends to improve after day 3, which could be the result of the reduced emetogenicity of the combination FEC with time. Altogether, 77% had good control of acute emesis; control of delayed emesis was better with 84% achieving a major response on day 2 after chemotherapy, which improved to more than 90% after day 4. Granisetron was generally tolerated with headache being the most common side-effect followed by constipation and flushing. This study suggests that granisetron is an effective and well-tolerated anti-emetic agent, which deserves randomised trials to elucidate its efficacy further.     

A nonlethal conditioning approach to achieve engraftment of xenogeneic rat bone marrow in mice and to induce donor-specific tolerance

BACKGROUND: The supply of solid organs for transplantation will never meet the growing demand. Xenotransplantation is considered to be a potential solution for the critical shortage of allografts. However, xenograft rejection is currently not controlled by conventional immunosuppressive agents. Bone marrow chimerism induces donor-specific tolerance without the requirement for chronic immunosuppressive therapy. The aim of this study was to develop a nonlethal recipient-conditioning approach to achieve mixed bone marrow chimerism and donor-specific tolerance. METHODS: C57BL/10SnJ mice were conditioned with total body irradiation followed by a single injection of cyclophosphamide on day +2. On day 0, mice were reconstituted with untreated bone marrow cells from Fischer 344 rats. Recipients were analyzed by flow cytometry for donor bone marrow engraftment and multilineage chimerism. Donor-specific tolerance was tested by skin grafting. RESULTS: One hundred percent of recipients engrafted after irradiation with 600 cGy total body irradiation, transplantation with 80 x 10(6) Fischer 344 bone marrow cells, and injection with 50 mg/kg cyclophosphamide intraperitoneally. Donor chimerism was detectable in all engrafted animals for up to 11 months. This conditioning was nonlethal, because conditioned untransplanted animals survived indefinitely. Mixed xenogeneic chimeras were tolerant to donor-specific skin grafts but rejected third-party (Wistar Furth) grafts as rapidly as naive C57BL/10SnJ mice. In contrast, animals that received less efficacious conditioning regimens and did not exhibit detectable chimerism showed prolonged graft survival, but delayed graft rejection occurred in all animals within 10 weeks. CONCLUSION: The induction of bone marrow chimerism and donor-specific tolerance after nonlethal conditioning might be useful to prevent the vigorous cellular and humoral rejection response to xenografts.